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Article
| Open Access
Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains
IgG3 antibodies have potent effector functions, but are not used as therapeutics and structural data are missing. Here, the authors combine cryoEM and MS to study IgG3-mediated complement activation to provide the first structural insights into IgG3.
- Leoni Abendstein
- , Douwe J. Dijkstra
- & Thomas H. Sharp
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Article
| Open Access
Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model
Migrasomes are recently discovered extracellular vesicles that are produced during cellular migration. Here, the authors show that macrophage-derived migrasomes are implicated in the progression of cerebral amyloid angiopathy (CAA) through increased complement signaling using skin biopsies from CAA patients and CAA mouse models.
- Mengyan Hu
- , Tiemei Li
- & Wei Cai
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Article
| Open Access
A ZFYVE21-Rubicon-RNF34 signaling complex promotes endosome-associated inflammasome activity in endothelial cells
NLRP3 inflammasomes trigger release of IL-1 to promote tissue injury. Here, Li et al identify a ZFYVE21-Rubicon-RNF34 (ZRR) signaling complex localizing to endosomes and modulating complement-mediated inflammasome activity in vitro and in vivo.
- Xue Li
- , Quan Jiang
- & Dan Jane-wit
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Article
| Open Access
Cryo-EM structures of Trypanosoma brucei gambiense ISG65 with human complement C3 and C3b and their roles in alternative pathway restriction
African Trypanosomes have developed elaborate immune evasion mechanisms. Here, the authors present the cryoelectron microscopy structures of a trypanosome surface receptor with human complement C3 and C3b, revealing several modes of complement interaction.
- Hagen Sülzen
- , Jakub Began
- & Sebastian Zoll
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Article
| Open Access
Helicobacter pylori initiates successful gastric colonization by utilizing L-lactate to promote complement resistance
The complement system is a key protective response against infectious pathogens. Here, the authors show that Helicobacter pylori uses host L-lactate to generate a complement resistant state that promotes gastric colonisation.
- Shuai Hu
- & Karen M. Ottemann
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Article
| Open Access
Structural basis for membrane attack complex inhibition by CD59
CD59 protects human cells from damage by the MAC immune pore. The authors show how CD59 inhibits MAC, by deflecting pore-forming β-hairpins of complement proteins. As well as how the membrane environment influences the role of CD59 in complement regulation and in host-pathogen interactions.
- Emma C. Couves
- , Scott Gardner
- & Doryen Bubeck
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Article
| Open Access
The classical pathway triggers pathogenic complement activation in membranous nephropathy
It is generally thought that complement activation in human membranous nephropathy (MN) occurs predominantly via the lectin or alternative pathway. Here, the authors show that the classical pathway is the dominant form of complement activation in MN and a pathogenic driver of the disease.
- Larissa Seifert
- , Gunther Zahner
- & Nicola M. Tomas
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Article
| Open Access
Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors
Therapeutic modulation of the complement system has gained interest over the past two decades. Here, the authors provide molecular-level insight into the mode-of-action, target selectivity and species specificity of the compstatin family of complement inhibitors, which entered the clinic in 2021.
- Christina Lamers
- , Xiaoguang Xue
- & Daniel Ricklin
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Article
| Open Access
Cryo-EM structures of human A2ML1 elucidate the protease-inhibitory mechanism of the A2M family
A2ML1 is a human protease inhibitor belonging to the A2M protein family. In this study, the authors determine structures of A2ML1 before and after protease inhibition and investigate its mechanism of action.
- Nadia Sukusu Nielsen
- , Alessandra Zarantonello
- & Jan J. Enghild
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Article
| Open Access
The crystal structure of iC3b-CR3 αI reveals a modular recognition of the main opsonin iC3b by the CR3 integrin receptor
Complement activation on foreign cell surfaces leads to the generation of complement opsonins, which activate complement receptor type 3 (CR3) and pathogen clearance by macrophages. Here, the authors reveal structural basis of the interaction between human opsonin iC3b and the von Willebrand A inserted domain of the α chain of CR3.
- Francisco J. Fernández
- , Jorge Santos-López
- & M. Cristina Vega
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Article
| Open Access
Structural basis of soluble membrane attack complex packaging for clearance
To prevent unregulated complement activation, extracellular chaperones capture soluble precursors to the membrane attack complex (sMAC). Here, structural analysis of sMAC reveals how clusterin recognizes heterogeneous sMAC complexes and inhibits polymerization of complement protein C9.
- Anaïs Menny
- , Marie V. Lukassen
- & Doryen Bubeck
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Article
| Open Access
C3 complement inhibition prevents antibody-mediated rejection and prolongs renal allograft survival in sensitized non-human primates
Donor-specific antibodies in sensitized recipients may cause kidney transplant rejection. Here the authors show that complement component C3 inhibition prolongs graft survival by inhibiting T and B cell proliferation/activation and hence tissue injury, despite antibody levels remaining unaffected.
- Robin Schmitz
- , Zachary W. Fitch
- & Stuart J. Knechtle
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Article
| Open Access
Dendrimer end-terminal motif-dependent evasion of human complement and complement activation through IgM hitchhiking
Understanding nanomaterials interactions with complement is important for a number of applications. Here, the authors study the interaction of sub 6 nm dendrimers with complement and show the small dendrimers escape complement activation but do interact with IgM to trigger lectin-pathway complement activation.
- Lin-Ping Wu
- , Mario Ficker
- & Seyed M. Moghimi
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Article
| Open Access
A SARS-CoV-2 antibody curbs viral nucleocapsid protein-induced complement hyperactivation
While SARS-CoV-2 S protein targeting monoclonal antibodies (mAbs) are well studied, little is known about N protein-targeting mAbs. Here, Kang et al. provide the crystal structure of the N protein RNA binding domain with a mAb derived from a convalescent patient and show that it compromises the N protein-induced complement hyperactivation.
- Sisi Kang
- , Mei Yang
- & Shoudeng Chen
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Article
| Open Access
ZFYVE21 is a complement-induced Rab5 effector that activates non-canonical NF-κB via phosphoinosotide remodeling of endosomes
Complement activation contributes to vascular inflammation in the contexts of allograft rejection and connective tissue disease. Here Fang et al. identify ZFYVE21 as a novel effector of Rab5 and find it regulates pro-inflammatory NF-κB signaling in endothelial cells in response to complement activation.
- Caodi Fang
- , Thomas D. Manes
- & Dan Jane-wit
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Article
| Open Access
Single-molecule kinetics of pore assembly by the membrane attack complex
The membrane attack complex (MAC) is a hetero-oligomeric protein assembly that kills pathogens by perforating their cell envelopes. Here, the authors use atomic force microscopy to show that MAC proteins oligomerize within the membrane, allowing them to identify the kinetic bottleneck of MAC formation.
- Edward S. Parsons
- , George J. Stanley
- & Bart W. Hoogenboom
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Article
| Open Access
CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers
The complement membrane attack complex (MAC) is a lytic immune pore that kills pathogens. Here the authors use cryoEM to provide a structural and biophysical mechanism for how β-pore forming proteins breach the lipid bilayer, providing pathways to explore pore-formation in molecular detail.
- Anaïs Menny
- , Marina Serna
- & Doryen Bubeck
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Article
| Open Access
Human antibodies targeting Zika virus NS1 provide protection against disease in a mouse model
Zika virus infection can cause severe disease in humans and there are currently no specific treatments or vaccines. Here, Bailey et al. isolate antibodies recognizing non-structural protein NS1 and show that they protect mice from disease by an Fc-dependent, non-neutralizing mechanism.
- Mark J. Bailey
- , James Duehr
- & Gene S. Tan
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Article
| Open Access
Complement receptor CD46 co-stimulates optimal human CD8+ T cell effector function via fatty acid metabolism
Complement, while serving to remove pathogens in the circulation, is also important for synergizing with inflammasomes to modulate CD4 T cell activation. Here the authors show that CD46, a complement receptor expressed only in humans, is essential for inducing optimal activation and effector functions of human CD8 T cells.
- Giuseppina Arbore
- , Erin E. West
- & Claudia Kemper
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Article
| Open Access
The first transmembrane region of complement component-9 acts as a brake on its self-assembly
The Complement component 9 (C9) is the pore-forming component of the Membrane Attack Complex which targets pathogens. Here authors use structural biology to compare monomeric C9 to C9 within the polymeric assembly and identify the element which inhibits C9 self-assembly in the absence of the target membrane.
- Bradley A. Spicer
- , Ruby H. P. Law
- & Michelle A. Dunstone
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| Open Access
Complement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking
Regeneration of skeletal muscle is accompanied by a transitory inflammatory phase. Here the authors show that the complement C3 component is activated following muscle injury, and signals through the alternative complement pathway to regulate immune cell infiltration and muscle regeneration.
- Congcong Zhang
- , Chunxiao Wang
- & Jie Du
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Article
| Open Access
Transitional changes in the CRP structure lead to the exposure of proinflammatory binding sites
C-reactive protein is a pentameric protein secreted by the liver in response to injury and infection. Here Braiget al. show that conformational changes in CRP on the surface of monocyte-derived microvesicles enable binding of complement C1q and lead to activation of the complement cascade and aggravation of inflammation.
- David Braig
- , Tracy L. Nero
- & Steffen U. Eisenhardt
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Article
| Open Access
Structural basis of complement membrane attack complex formation
The membrane attack complex (MAC) is an immune effector that kills pathogens by forming pores in their membrane. Here the authors use cryo-electron microscopy to reveal that the full MAC is an asymmetric pore with a split-washer configuration and identify a network of interactions that provide a basis for sequential assembly.
- Marina Serna
- , Joanna L. Giles
- & Doryen Bubeck
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Article
| Open Access
CTRP6 is an endogenous complement regulator that can effectively treat induced arthritis
The complement system contributes to chronic inflammatory diseases. Here the authors show that CRTP6 suppresses the alternative complement pathway and reverses rheumatoid arthritis in a mouse model of the disease.
- Masanori A. Murayama
- , Shigeru Kakuta
- & Yoichiro Iwakura
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Article
| Open Access
Structural basis for the targeting of complement anaphylatoxin C5a using a mixed L-RNA/L-DNA aptamer
Spiegelmers are mirror-image oligonucleotide aptamers designed for therapeutic use. Here the authors describe the crystal structure of the mixed L-RNA/L-DNA Spiegelmer NOX-D20 bound to complement component C5a, a key mediator of the innate immune response and clinical target in acute and chronic inflammatory disorders.
- Laure Yatime
- , Christian Maasch
- & Axel Vater
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Article
| Open Access
Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling
The role of macrophages in hypertension-induced arterial remodeling is poorly understood. Here, Sumida et al. show that high blood pressure drives the alternatively activated macrophages to secrete complement C1q protein, which in turn elicits proliferative β-catenin signalling in the arterial smooth muscle cells.
- Tomokazu Sumida
- , Atsuhiko T. Naito
- & Issei Komuro
Human IgG Fc-engineering for enhanced plasma half-life, mucosal distribution and killing of cancer cells and bacteria